Abstract
Epothilones, produced from the myxobacterium Sorangium cellulosum, are potential anticancer agents that stabilize microtubules in a similar manner to paclitaxel. The entire epothilone biosynthetic gene cluster was heterologously expressed in an engineered strain of Streptomyces venezuelae bearing a deletion of pikromycin polyketide synthase gene cluster. The resulting strains produced approximately 0.1 μg/l of epothilone B as a sole product after 4 days cultivation. Deletion of an epoF encoding the cytochrome P450 epoxidase gave rise to a mutant that selectively produces 0.4 μg/l of epothilone D. To increase the production level of epothilones B and D, an additional copy of the positive regulatory gene pikD was introduced into the chromosome of both S. venezuleae mutant strains. The resulting strains showed enhanced production of corresponding compounds (approximately 2-fold). However, deletion of putative transport genes, orf3 and orf14 in the epothilone D producing S. venezuelae mutant strain, led to an approximately 3-fold reduction in epothilone D production. These results introduce S. venezuelae as an alternative heterologous host for the production of these valuable anticancer agents and demonstrate the possibility of engineering this strain as a generic heterologous host for the production of polyketides and hybrid polyketide-nonribosomal peptides.
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Acknowledgments
This work was supported by the Korea Science and Engineering Foundation (KOSEF) funded by the Korea government (MEST) (R11-2005-008-00000-0), the National Research Laboratory (NRL) program grant (R0A-2008-000-20030-0), the Marine and Extreme Genome Research Center Program of the Ministry of Land, Transportation and Maritime Affairs, Republic of Korea, and grants from the National R&D Program for Cancer Control (0620300-1).
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Park, S.R., Park, J.W., Jung, W.S. et al. Heterologous production of epothilones B and D in Streptomyces venezuelae . Appl Microbiol Biotechnol 81, 109–117 (2008). https://doi.org/10.1007/s00253-008-1674-0
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DOI: https://doi.org/10.1007/s00253-008-1674-0